During the last decade, chemokines and their receptors have emerged as important signaling molecules in processes regulating neuronal migration, cell proliferation, synaptic transmission, neuronal inflammation and degeneration. Chemokine receptors, CXCR4 and CCR5, act as coreceptors for HIV-1, drawing attention to this intriguing class of immune mediators. Epidemiological data connecting HIV-1 associated dementia to drug of use, particularly methamphetamine (METH), suggest that stimulants may enhance HIV-1 neurotoxicity. Although the mechanism(s) of this neurotoxic synergism is not fully understood, METH may alter neural immune responses that could play a role in its pharmacology, including neurotoxicity, or contribute to the neuronal effects of other factors. Whether and how METH modulates immune function in brain is not known. Astrocytes express chemokines and their receptors and they may be key players in the regulation of chemokine system in CMS. Studies suggest astrocytes contribute to the pathogenesis of lentiviral encephalopathy and METH enhances viral infectivity of astrocytes via chemokine receptors. My hypothesis is that METH modulates chemokine function in astrocytes, and in doing so alters their ability to act as buffer system to maintain brain homeostasis impacting plastic and pathologic responses. Primary astrocytes are used as a model to investigate the effects of METH and other stimulants on chemokine responses and their role in astrocyte function. In this regard, the following Specific Aims will be investigated: Aim 1: To explore the effects of METH on chemokines, their receptors and signaling pathways. Aim 2: To determine the effects of METH on astrocyte proliferation and phenotype, and the role of chemokines. [unreadable] [unreadable]